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"...health will finally be seen not as a blessing to be wished for, but as a human right to be fought for." Kofi Annan

Nymphomaniac: a woman as obsessed with sex as an average man. Mignon McLaughlin

HIV is certainly character-building. It's made me see all of the shallow things we cling to, like ego and vanity. Of course, I'd rather have a few more T-cells and a little less character. Randy Shilts

ANN,I just tried it again and it worked for me. All I did was single click on the link. In short the link takes you to apatent application by the researches at DUKE university. DUKE is where the headquarters of CHAVI (commitee of hiv and aids vaccine initiative) is located. CHAVI is aglobal initiative in conjunction with CAVD,IAVI and more than 40 researches and 9 institutions backed by the patronage of Bill and Melinda Gates foundation to find a cure and a vaccine. The patent is 97 pages of wonderful !! Please try again and I'lll try to find another link.

"...health will finally be seen not as a blessing to be wished for, but as a human right to be fought for." Kofi Annan

Nymphomaniac: a woman as obsessed with sex as an average man. Mignon McLaughlin

HIV is certainly character-building. It's made me see all of the shallow things we cling to, like ego and vanity. Of course, I'd rather have a few more T-cells and a little less character. Randy Shilts

If the link worked for you, go to the top of the right side of the page and you will see a box that says pdf page by page. Click on the down arrow that shows pdf 97 pages. Click on 97 pages and it should come up for you. Let me know.

Your response to me made me realise that the patent is not an easy read without the background research needed to understand the method of action of this new paradigm. Reading a pdf file can be daunting and I thankyou for pointing this out. Let me try to paraphrase the invention and if there are any science-types out there who have read the patent and understand the moa, I welcome any corrections.

Let me preface my statements by saying that I am not a scientist, professional researcher or doctor. I, like many of you, am tired of taking toxic drugs with all the accompanying sides, however, I am certainly thankful for the job that these drugs have done to extend life. My intention here is not to open my own bag of woe, but to show that research is proceeding at an amazing rate and that I believe a breakthrough is closer than we think.

This patent is based on anti-phosphilipid therapy (anti-ps). Phosphilipids are present in every cell in the human body, however, they are usually pointed inward to the cell providing among other things,nourishment to the cell. When a cell is about to die (apoptosis) these phosphilipids turn outward and eventually the dead cells are removed. The immune system recognizes this as a normal process and leaves these cells alone until they are dead. When a virus (like HIV) enters a cell this same phosphipid flip occurs however the cell does not die immediately tricking the immune system into thinking this a natural occurring process. Also these phosphlipids are providing nourisment to the virus. When the virus breaks out, it takes along some of these phosphilipids for its own use and they are also pointing outward on the virus protecting the virus from the immune system. Dr. Haynes et al. have found that certain broadly neutralising antibodies (ie:4e10,2f5,is1 among others) are able to recognize this deception by the virus and go in for the kill. These antibodies are also able to go after those cells infected with the virus leaving normal apoptosis alone.

The work is brilliant and elegant and many components have already been tested both preclinically and clinically. I refer you to the chavi.org to view the clinical trials comprising some of the components that have been tested. For those of you that are so inclined, you can look up the reseach of the principal investigators on pub med. It's adaunting task!

My explanation herein is certainly elementary but I have tried to give all as simple an explanation as I can. Again, if anyone can see any errors or corrections please don't hesitate to correct me. By the way, the vaccine teaches your immune system to do the job on its own.Please forgive me for the long post.

Submitted September 22, 2008Our goal is to acquire proof of concept data that manipulation of the immunoregulatory controls of B cell immune responses to HIV-1 Env, coupled with enhanced immunogen design, can lead to safe induction of broadly reactive neutralizing antibody responses. We are using a two armed approach to the problem of induction of antibodies that broadly neutralize HIV.

The Kelsoe, Haynes and Thorpe laboratories are developing immunogen formulations that trigger B cells normally tolerant to the desired Envelope epitopes and regions. Garnett Kelsoe is determining the origins, development, physiology, and fates of marginal zone, transitional and B1 B cell populations in animal models including mice and non-human primates. Haynes is determining the role of tolerance mechanisms, and TLR signaling on control of broadly reactive B cell activation, and Philip Thorpe is determining the role of lipid binding of anti-HIV antibodies and anti-phosphatidylserine (PS) autoantibodies to protection from HIV infection. We have completed the first protection trial to determine if anti-beta-2-glycoprotein-1 antibodies can prevent infection or early viral destruction of the immune system in acute SIV infection and these pathogenic anti-lipid antibodies do not prevent HIV-1 and SIV infection in vitro and do not protect against SIV-1 infection in vivo. The team has recently found that non-pathogenic anti-lipid antibodies that do not require beta-2-glycoprotein-1 for lipid binding do prevent HIV-1 and SHIVSF162P3 (and all R5 HIVs tested from infecting PBMC in vitro, and a prototype of non-pathogenic anti-lipid antibodies will be studied in vivo for the ability to protect against R5 SHIV infection.

The Harrison, Alam, Spicer, Shaw, Robinson and Hahn laboratories are developing immunogens that are in native conformations and are being tested for induction of neutralizing antibodies. These include HIV Env immunogens with a spectrum of affinities for binding to broadly reactive neutralizing antibodies, and immunogens with low entropic barriers to Mab binding and therefore are thermodynamically stable. Steve Harrison, Bing Chen and Larry Liao have made single chain Fv 4E10 antibodies and whole IgG1 2F5 Mabs with mutations that selectively eliminate gp41 or lipid reactivity. They have demonstrated that both 2F5 and 4E10 require the capacity to bind to lipids to neutralize HIV-1. They will now use the Fvs and Mabs in co-crystallization efforts with trimeric gp120/gp41 constructs. Munir Alam has designed gp41 peptide lipid conjugates using 4E10 and 2F5 epitopes peptides. He is characterizing the binding kinetics, and thermodynamic properties of 4E10 and 2F5 binding to peptide-lipid conjugates. Heather Desaire is characterizing the carbohydrates of HIV-1 Env produced in T cells and macrophages, and Haynes is determining methods for making these “autoantigens” immunogenic. Spicer is studying the lipid-peptide conjugates for their structures by NMR. George Shaw and Beatrice Hahn have constructed HIV-1/HIV-2 chimeras with HIV-2 neutralizing determinants in HIV-1 scaffolds, to study the neutralization of HIV-2 with James Robinson . The Team led by Victor Chalwe at the Tropical Disease Research Laboratory in Ndola, Zambia is providing the CAVD with PBMC and plasma on a series of chronically infected subjects for mapping epitopes of broadly neutralizing antibodies for immunogen design.

Ok, let's talk about these WONDER-DRUGS. Panitumumab ("Vectibix"), for instance, a monoclonal antibody "for the treatment of patients with colorectal cancer that has metastasized following standard chemotherapy".

"The mean time to disease progression or death in patients receiving Vectibix was 96 days versus 60 days in patients receiving the best standard supportive care. [...] Both study groups showed similar overall survival."(Let alone dermatological side effects)

that is silly to say that a monoclonal antibody for cancer is worthless -- a monoclonal antibody is like a wrench or a screw driver it is a tool to heal the body, the mechanic needs lots of tools and development of a new tool is a good thing

science is still in its infancy in the use of monoclonal antibodies for cancer, some day there may be a triple cocktail of monoclonal antibodies for a specific cancer with 99% cure rate like the HIV HAART triple cocktail

you are taking one tiny step in science and trying to burn at the stake all science progress,

it is like man learning how to fly -- man saw the wings of birds for thousands of years and dreamed and then slowly they figured out the Wright brothers wing then it took millions of men working to innovate the metal airplane and the jet engine etc.

as i have said before, the immune system is a complex system, it is more than the SUM of its parts

cancer -- and this was discovered a few weeks ago is not simple like HIV -- science had hoped that it was a few genes that went wrong in same way, the new discovery is cancer is

thousands of genes going wrong in millions of ways so there are trillions of different kinds of cancer -- anotehr way to look at it is everyone has thier own unique cancer based on thier own unique genes

that is silly to say that a monoclonal antibody for cancer is worthless -- a monoclonal antibody is like a wrench or a screw driver it is a tool to heal the body, the mechanic needs lots of tools and development of a new tool is a good thing

Well, when the mechanic has ALL the necessary tools, he will start his workshop. Until then, he CANNOT ask to be paid 7,763.745$ a day for his badly made jobs.

Both of you have some very good points. The cost of some of these medications are outrageous with a somewhat less than satisfactory side affect profile and not much life extension. But as bimazek points out you have to start somewhere.

This is why I am hopeful about anti-ps. In the phase 1 clinical trials for Bavituximab for cancer and Hep C the mab had top line safety data and some efficacy(phase 1). Cancer cells also flip phosphilipids. Hiv iis a retrovirus like Hep C so the mab should do the same for Hiv. I anxiously await the interim data from the co-infection trial of Hep C and HIV with Bavituximab. I posted this clinical trial in an earlier reply.

The July announcement by NIAID Director Dr. Anthony Fauci to scrap the upcoming "PAVE-100" HIV vaccine clinical trial, (following on the heels of the failed Merck "STEP" HIV vaccine trial), showed yet again how difficult and elusive the goal of an effective HIV vaccine remains.

In the midst of these sobering developments, an important new insight was gained into why experimental HIV vaccines have failed to elicit an adequate immune response. The discovery, published in the August issue of the Journal of Virology (1), came from the leader of NIAID's “CHAVI” organization, Dr. Barton Haynes of Duke University, who is also a principle investigator of the Gates Foundation HIV vaccine effort.

In their paper, Haynes and colleagues discuss experiments showing that HIV weakens the immune system much faster than previously thought. The primary mechanism responsible for this immunosuppression is an overwhelming amount of what Haynes terms "microparticles", which are tiny particles shed from the outer membranes of infected and dying cells. This cellular debris accumulates during early HIV infection, and circulates throughout the body blunting the functions of the immune cells that would ideally fight the virus. Popular news articles have discussed this aspect of the Duke researchers' findings, but the details and broader implications of the team's discovery have yet to be elucidated in the media.

The paper explains that the microparticles contain the molecule phosphatidylserine (PS) exposed on their surface. PS is a lipid that normally lines the interior of the cell membranes of every cell in our body. As a cell dies, it loses the ability to maintain PS on the inside of the cell membrane. The PS flips to the exterior, where it is perceived by immune cells as a sign of a dying native cell. The Haynes team cite recent data showing how exposed PS appears to be the fundamental signal that shifts the behavior of immune cells into not mounting an antigen-specific attack, since PS is interpreted as a sign of “self” rather than a foreign invader (2). Other researchers have also recently illustrated the suppressive effects of PS on macrophages, the resulting cytokine environment, dendritic cells, and T cells (3-7). It is thus no surprise that recent research has also revealed exposed PS as a feature common to many diverse pathogens (8-22), as if they independently evolved to exploit a similar mechanism of evasion, since it provides the crucial advantage of triggering an inappropriate immune response, facilitating the pathogen's survival and proliferation.

A review of Haynes' recent patent applications provides further details that have yet to be published in the journals. In one application, titled “Multicomponent Vaccine” (23), Haynes explains that any future successful HIV vaccine must interrupt this PS-mediated immunosuppressive signaling. A specific goal mentioned is for a vaccine to induce antibodies to PS (anti-PS), thereby blocking the overwhelming immune suppression seen in the Duke research, allowing the viral immunogen in the vaccine the chance to evoke T and B cells which effectively fight the virus.

In yet another recent patent application, Haynes proposes using anti-PS as a promising treatment for people already infected with the virus (24). He discusses the ability of anti-PS monoclonal antibodies to bind to HIV and HIV-infected cells, saying anti-PS "can be safely used as a therapeutic Mab for treatment of HIV infected subjects", and that it can "broadly neutralize HIV in an unprecedented manner".

Perhaps the most fascinating comment found in one of Haynes' many recent patent applications is his suggestion that HIV's method of immune evasion may be a general escape mechanism utilized by other pathogens (24), and that similar means of therapy may be effective against other diseases. Indeed, a review of the recent major journals corroborates this concept:

In April, the journal Science published experiments showing that the pox family of viruses, (vaccinia), utilize exposed PS to gain entry into cells (25).

In the March issue of the journal Clinical Cancer Research, scientists from Harvard University discuss experiments in which blocking PS signaling helped facilitate complete melanoma tumor regressions (26).

The protozoan parasites responsible for many of the deadly diseases affecting much of the developing world have been found to rely on exposed PS to successfully avoid the immune system of their host (16-22).

Several cancer researchers have recently published data which bears a striking resemblance to the new findings of the Haynes HIV group, showing a very similar method of systemic immune suppression caused by PS-exposing microparticles shed from tumor cells (29-34), (see also 27, 28).

In another recent Haynes patent application he also discusses PS-exposing microparticles as playing a role in the pathogenesis of several auto-immune diseases as well as atherosclerosis (35), (see also 36-40).

Taken together, these discoveries suggest a new immunological perspective of pathogenesis in general. A paradigm appears to be emerging in which the necessary and admirable flexibility of the immune system has been exploited precisely where it is most vulnerable – when it must commit to a 'friendly' response. The recent HIV research by Haynes and colleagues, focusing on PS-induced immune suppression, and the safe therapeutic targeting of exposed PS with antibodies, carries implications of unprecedented broad therapeutic potential.

20. Annalena Bollinger, 2005, Leishmania Major Promastigotes Use Phosphatidylserine For Silencing Of Polymorphonuclear Neutrophils Doctoral dissertation in partial fulfillment of the requirements for the degree of Doctor of Natural Sciences (Dr. rer. nat.) from the University of Lübeck - Faculty of Technology and Sciences

Leit,Coupling current findings with data from earlier studies, Barton Haynes, MD, Director of CHAVI and the senior author of the study, believes that a successful vaccine would have to create immunity that would precede the time of infection, a process that might also involve manipulating the earliest antibody response and then sparking the stronger, broadly neutralizing response that normally occurs at a much later time in natural infection.

"We are encouraged by these findings," says Haynes. "The pace of discovery is picking up and the pieces of the puzzle are coming together. Little by little we are learning more about the very earliest stages of HIV infection and a getting a clearer picture of what a successful vaccine will have to do."

The topic hasn't changed. This research is part of the vaccine antibody research being done at Duke. The quote above is the clue.

Autoimmune disease patients can make antibodies that, in some capacity, have the ability to neutralize HIV-1 , either in binding to the HIV envelope or in binding to lipids on the surface of the virion, or both. Moreover autoimmune disease patients can make a protective neutralizing type antibody either constitutively or after HIV-1 infection.

The invention also includes antibodies from normal subjects and from autoimmune disease patients that do not react HIV envelope but rather with virus-infected cells and or virions, that is, they bind to lipid on the virus or virus-infected cells (see Example 6).

Example 6

Human monoclonal antibodies (termed CL1 , IS4 and IS6) derived from patients with anti-phospholipid syndrome have been studied.IS4 and IS6 are pathogenic anti-lipid antibodies whereas CL1 is a non-pathogenic anti-lipid autoantibody (Table 4). Whereas none of these antibodies neutralized HIV pseudoviruses in the pseudovirus inhibition assay that reflects primarily infection by virion-cell fusion (Li et al, J. Virol. 79:10108-25 (2005) (Table 5), all three of these antibodies neutralized HIV-1 in the PBMC HIV neutralization assay that depends on endocytosis of HIV and is a mirror of HIV infectivity of CD4 cells in vivo (Table 6). That CL1 neutralized HIV evidences the facts that: a) humans can make non-pathogenic anti-lipid antibodies that neutralize HIV, and b) CL1 is an antibody that can be safely used as a therapeutic Mab for treatment of HIV infected subjects or in the setting of postexposure prophylaxis of subjects following needle, sexual or other exposure to HIV or HIV infected materials.

Alving and colleagues have made a mouse mab against phosphatidyl inositol phosphate and have shown that it neutralizes HIV in a PBMC assay (Wassef et al, MoI. Immunol. 21 : 863-868 (1984), Brown et al, Virol. 81 : 2087-2091 (2007), Beck et al, Biochem. Biophys Res. Comm. 354: 747-751 (2007)). What the present studies show is that humans can spontaneously make anti-lipid antibodies and that these antibodies can broadly neutralize HIV in an unprecendented manner.

Summarizing, autoimmune disease patients can make antibodies that bind to virus-infected cells and, presumably, to budding HIV virions by virtue of their reactivity to HIV membranes and host membranes. Certain anti-lipid antibodies from autoimmune disease patients can also react with the Envelope trimer (such as IS6) but not all of the antibodies react also with the trimer (i.e., CL1 and IS4 do not react). Therefore, reactivity with the HIV envelope is not a prerequisite for neutralization in these antibodies.

These studies also demonstrate that it may be possible to safely stimulate the production of CL1 like antibodies in humans using gp41 lipid complexes (Alam et al, J. Immunol. 178:4424-4435 (2007), Schuster et al, J. Immunol. 122:900-905 (1984)).

I agree with you John. They should have gone after HIV right away. My only guess is that CHAVI was very interested in these mabs for both a cure and a vaccine and they had the financial backing to do the necessary research. I believe we will be hearing a lot more about anti-ps in the very near future. I hope CHAVI has a homerun to report. Everyone needs their pound of flesh! IMHO.(there is a lot more to this than the obvious).

Bavituximab is in clinical trials for the treatment of hepatitis C virus (HCV) infection and in preclinical development for the treatment of viral hemorrhagic fevers under a contract worth up to $44.4 million with the bioterrorism program of the U.S. Defense Threat Reduction Agency (DTRA). Bavituximab and other anti-PS antibodies are also being studied preclinically in HIV, cytomegalovirus (CMV) and other serious viral infections.

"Based on these findings, anti-PS antibodies such as bavituximab may represent a completely new class of drugs for the treatment of life-threatening viral infections," said study co-author Dr. Philip Thorpe, professor of pharmacology at UT Southwestern Medical Center and a scientific advisor to Peregrine. "By targeting a property of the host cell rather than the virus itself, anti-PS antibodies have the potential to treat a range of viral infections, and they should be less susceptible to the viral mutations that contribute to the development of drug resistance."

In the research reported today, scientists at UT Southwestern assessed the activity of bavituximab in animal models of two lethal viruses --cytomegalovirus and Lassa fever virus, a hemorrhagic fever virus that is listed as a class A bioterrorism agent by the CDC. Bavituximab showed potent anti-viral activity in both models.

Dr. Melina Soares, lead study author and UT Southwestern instructor of pharmacology, commented, "Recent non-affiliated research has further confirmed that exposed PS has immunosuppressive properties and is also clarifying its involvement during viral infection of cells. Our data go a step further, providing compelling evidence that exposed PS itself is a promising anti-viral drug target that is involved in the pathogenesis of multiple viruses, suggesting the possibility of achieving broad-spectrum anti-viral effects using a single anti-PS agent. We look forward to further exploring the potential of bavituximab and other anti-PS antibodies against viruses for which there are few or no effective therapeutic options."

In the first study, 100% of mice infected with lethal murine CMV and treated with bavituximab recovered fully, while only 25% of control animals survived. In the second study, guinea pigs were infected with lethal Pichinde virus, which is a model virus for Lassa fever. Fifty percent of the bavituximab-treated group survived, while untreated animals all died. In this study, the anti-viral effect of bavituximab was further augmented by the addition of the standard of care drug ribavirin, with 63% of animals receiving the combination therapy surviving the potentially lethal infection.

"We are extremely pleased to see this research demonstrating the broad anti-viral potential of bavituximab and our anti-PS technology platform published in this highly regarded journal," said Steven W. King, president and CEO of Peregrine. "This new publication is the latest in a series of external validations of our anti-viral program. It follows a recently awarded federal government contract for assessment of anti-PS antibodies to treat viral hemorrhagic fevers, research on the role of PS in viral infections that was published in a leading science journal earlier this year, and a recent presentation on anti-PS antibodies at a global HIV conference."

Anti-ps antibodies have already been tested in humans with top line safety data.

The virus cannot mutate against bavituximab because the antibody does not go after the virus itself. It attacks the exposed phosphalipid attached to the virion and also to the reservoir cell that the virus has infected. This phosolipid flip on these cells are a primary function of the cell that occurs throughout the body when cells die. In order for the virus to escape this mechanism it would have to evolve to a different life cycle and that won't happen in our life time.

There is a pressing need for antiviral agents that are effective against multiple classes of viruses. Broad specificity might be achieved by targeting phospholipids that are widely expressed on infected host cells or viral envelopes. We reasoned that events occurring during virus replication (for example, cell activation or preapoptotic changes) would trigger the exposure of normally intracellular anionic phospholipids on the outer surface of virus-infected cells. A chimeric antibody, bavituximab, was used to identify and target the exposed anionic phospholipids. Infection of cells with Pichinde virus (a model for Lassa fever virus, a potential bioterrorism agent) led to the exposure of anionic phospholipids. Bavituximab treatment cured overt disease in guinea pigs lethally infected with Pichinde virus. Direct clearance of infectious virus from the blood and antibody-dependent cellular cytotoxicity of virus-infected cells seemed to be the major antiviral mechanisms. Combination therapy with bavituximab and ribavirin was more effective than either drug alone. Bavituximab also bound to cells infected with multiple other viruses and rescued mice with lethal mouse cytomegalovirus infections. Targeting exposed anionic phospholipids with bavituximab seems to be safe and effective. Our study demonstrates that anionic phospholipids on infected host cells and virions may provide a new target for the generation of antiviral agents.

For years scientists have tried to combat viruses through the design of drugs targeting various molecules belonging to the viruses themselves. As logical and as promising as this may sound, the strategy has achieved limited success.

A new paper published in the journal Nature Medicine, detailing experiments performed by scientists from the University of Texas working for Peregrine Pharmaceuticals Inc., has surprisingly shown that instead of targeting a viral molecule, drugs targeting a particular non-viral tag-along fat which viruses grab from our own cell's plasma membrane, may be the most effective way yet to combat viruses - many different viruses. This cell membrane material gets stuck to viruses as they exit cells. The same material becomes exposed specifically on virally-infected cells, but not on healthy cells. The U. of Texas and Peregrine Pharmaceuticals work published in Nature Medicine shows that using an antibody to target this host-cell fat can cure typically lethal viral infections.

As a virus exits one of our cells, whether it's an influenza virus, or HIV, deadly hemorrhagic virus, hepatitis C, herpes virus, or many others, each virus takes along a little of the cell's greasy perimeter membrane as a coat. Normally, as part of a healthy cell, this perimeter membrane is made up of well-organized lipid molecules, with negatively charged lipids, specifically one termed "phosphatidylserine" (PS), sequestered to the inside of the membrane. This organization of membrane lipids requires a certain amount of energy, and consequently such organized lipids are only maintained in healthy cells. Viruses lack the ability to keep the lipid "PS" on the inside of their stolen lipid membrane. Unlike healthy cells, viruses are wearing inside-out lipid coats, and so are the cells that viruses infect. The negatively-charged lipid "PS" is exposed. That's the target.

Influenza and influenza-infected cells wear the PS target. HIV and HIV-infected cells wear the PS target. So do herpes viruses, as well as dangerous hemorrhagic fever viruses, and many others.

Multiple viruses and virally-infected cells are all exposing the same lipid target.

The scientists designed an antibody, named Bavituximab (anti-PS), which is attracted to the negatively charged lipid PS. They found that the antibody binds to viruses and virally infected cells from multiple virus families. An antibody's job is to alert the immune system to destroy what it's attached to. In the case of anti-PS, the immune system is motivated to destroy the virus and virally-infected cells that expose PS. In the experiments detailed in Nature Medicine, animals receiving a lethal dose of a hemorrhagic fever virus were cured with anti-PS treatment. All animals not receiving anti-PS died from the infection.

Immunologists have found that exposed PS appears to provide a signal for a "host-friendly" immune response. Our own cells expose PS as a sign that they are dying. If a dying cell was left to decay in the body, it would eventually leak dangerous chemicals that could damage nearby cells, potentially causing a deadly cascade of cell death that could be harmful to the overall organism. Scientists have discovered that exposed PS appears to be the fundamental trigger for neighbor cells in the same organism as well as "professional" roving immune cells to perform a sort of "friendly clean-up". This clean-up procedure is much different from the way our immune system deals with what it perceives as foreign invaders. Exposed PS thus seems to send a signal to the cells of our immune system to NOT mount an attack. However, when the exposed PS is covered with the anti-PS antibody Bavituximab, it's as if the viruses and virally-infected cells are all wearing a big red flag, alerting the cells of the immune system to attack, and even to remain vigilant into the future to guard against any reappearance of the invader.

Concurrent to the recent insights gained by immunologists into the immuno-suppressive functions of exposed PS, scientists studying several different viruses have discovered that viruses contain PS exposed on their surface. The PS was taken from the cell they were 'born' from. Importantly, the most recent research, published in the journal Science, has demonstrated that the exposed PS on viruses is functional- it plays an essential part in the infection process. The PS is required for the virus to enter/infect new cells. Covering the PS, or removing the PS, prevents viral infection of cells.

These recent discoveries lead to a fascinating hypothesis. It seems that viruses have been taking advantage of our immune response to native dying cells. As multicellular organisms and viruses evolved together over time, successful viruses may have found and exploited our immune system's Achilles' heel. Now it seems that we may have found theirs, through targeting the very molecule that viruses have been stealing from the inside of our cell membranes to avoid an immune system attack.

led by Tony Moody, Director, Laboratory of B cell Immunology, Duke University

CHAVI 005 – Analysis of Host Response to HIV-1 in Autoimmune Disease Patients The purpose of this study is to test a hypothesis for why broadly reactive neutralizing antibodies are predominantly absent during AHI. This protocol will screen patients with autoimmune diseases such as lupus or Anti-Phospholipid Antibody Syndrome who are co-infected with HIV in order to study the quality of anti-HIV neutralizing antibodies. The hypothesis is that patients with B cell tolerance defects will be able to make more robust anti-HIV antibody responses. This study has been approved and is currently underway.

1. Purpose of the study- This is a cross-sectional study that analyzes the sera of subjects in order to answer two clinical questions. First, we will assay the antibody profiles of subjects with autoimmune diseases to determine if there is cross-reactivity with the HIV epitopes 2G12, 1b12, 2F5 and 4E10, in addition to analyzing B and T cells to assess patterns that contribute to autoimmunity and autoantibody reactivity. The second goal of the study is to assess the prevalence of HIV infection in a cross-sectional cohort of subjects with autoimmune disease.

2. Background & significance – After twenty years of study, the HIV epidemic continues to rage world-wide. Now over 40 million people are infected and an estimated 100 million will be infected by the year 2010 (1). A safe and effective HIV vaccine is desperately needed. HIV vaccines have proven extremely difficult to develop. One of the most urgent problems to solve is to induce antibodies that broadly neutralize HIV of all subtypes. To date, 4 human monoclonal antibodies that broadly neutralize HIV, termed 2G12, 1b12, 2F5 and 4E10, have been made from HIV infected subjects (2-4). Anti-2G12 targets a carbohydrate determinate on HIV envelope protein gp120. Anti-1b12 binds to an epitope on the CD4 binding site, and anti- 2F5 and anti-4E10 recognize membrane-proximal epitopes of the envelope protein gp41 near the surface of the virion.

A conundrum has developed with the observation that while multiple envelope immunogens express these epitopes on the surface of the envelope trimer, after injection into animals or man, the epitopes are not immunogenic. Moreover, most patients who are infected with HIV do not routinely make antibodies to these targets. Thus a major effort is to learn how to induce broadly reactive neutralizing antibodies against HIV by immunizing with these epitopes. Recently we have turned our studies to examine abnormalities in the host that may prevent a robust humoral immune response to these conserved HIV epitopes. We have speculated that a critical host factor could be that the 2G12, 1b12, 2F5 and 4E10 epitopes are also self-antigens. Consequently, if host B cells generate antibodies against these HIV epitopes, they are immediately deleted because the antibodies are autoreactive. Supporting evidence for this hypothesis from our group has shown that antibodies raised against 1b12, 2F5 and 4E10 have potent cross-reactivity for autoantigens including double stranded DNA, Ro, phospholipids, centromere B, topoisomerase and histones.

The association between autoimmune disease and infection with human immunodeficiency virus (HIV) has evolved over the past two decades. Initial observations described spontaneous improvement in conditions including systemic lupus erythematosus (SLE) in patients that developed AIDS as a consequence of HIV infection. Since the advent of highly-effective antiretroviral therapy, new-onset autoimmune diseases or relapse of previous autoimmune diagnoses have been observed after recovery of CD4+ T cell counts. Although it is consistent with the known pathophysiology of autoimmune disease that a reduction in immune function, whether by therapeutic intervention or retroviral infection, should decrease disease activity, little has been reported on the overall prevalence of HIV infection in patients with autoimmunity. In fact, relatively few cases of systemic lupus erythematosus, the prototypical systemic autoimmune syndrome, have been described in the literature. Moreover, there are no reports of HIV prevalence among cohorts of subjects with defined autoimmune disease. More recently, the sense has grown that subjects with autoimmune disease experience less HIV burden than would be expected of the general population.

These clinical and laboratory observations have led to an exciting postulate that perhaps patients with autoimmune disease are protected from HIV infection due to their intrinsic loss of self-tolerance. Whatever the defect in central and/or peripheral tolerance that leads to the emergence of autoimmune disease may also permit these patients to generate neutralizing (auto-)antibodies against the HIV epitopes described above. To investigate this proposition, we plan to assess for the prevalence of HIV infection in the cohort of autoimmune disease-afflicted patients cared for in the Duke Rheumatology Clinic (particularly, the Duke Lupus Clinic and Duke Scleroderma Research Center). In addition, we will examine the reactivity of sera from subjects with autoimmune diseases including SLE, systemic sclerosis, Antiphospholipid antibody syndrome, and Sjogren’s syndrome. Serum reactivity will be analyzed for a broad panel of autoantigens (centromere, topoisomerase, extractable nuclear antigens (Smith, ribonucleoprotein, Ro, and La), double-stranded DNA, cardiolipin (phospholipids), histones) and the HIV epitopes (2G12, 1b12, 2F5 and 4E10). In addition, all subjects will be tested for HIV infection with HIV PCR. These results will be compared with those obtained from a healthy control group (n=100). As part of the protocol, separated B cells will be sent to Dr. James Robinson of Tulane University for manufacture of hybridomas. This technique will generate B cells that make antibodies targeting various HIV envelope antigens. Dr. Robinson will use the hybridomas to sequence interesting B cell DNA for analysis of immunoglobulin gene structure. In addition, anonymized samples of serum will be sent to Dr. George Shaw at the University of Alabama, Birmingham for performing HIV-1 neutralization assays.

Bavituximab Anti-Viral represents a unique approach to treating viral diseases by recognizing features found only on infected cells and enveloped viruses. Bavituximab is a monoclonal antibody that binds to a basic component of the cell structure called an aminophospholipid that is exposed on the surface of cells only when they are infected with certain viruses or when they are malignant.

After binding to these infected cells, the drug alerts the body’s immune system to attack the infected cells. This makes infected cells particularly susceptible to bavituximab treatment, while potentially sparing healthy cells. Also, bavituximab binds to phospholipids which are derived from the host (human) cell and not the virus, which indicates it may not be susceptible to viral drug resistance. In addition to treating an active illness, bavituximab may also confer long-term immunity.

Peregrine has completed single and multiple ascending dose, monotherapy trials in patients with chronic HCV infection. Bavituximab infusion was generally well-tolerated and encouraging signs of anti-viral activity were seen at all dose levels tested. A Phase Ib study in patients co-infected with HCV and Human Immunodeficiency Virus (HIV) is now underway. This multi-center trial is designed to evaluate multiple doses of bavituximab for safety, pharmacokinetics and initial efficacy.

In pre-clinical experiments, Peregrine continues to evaluate bavituximab's potential for the treatment of several virus infections including influenza and HIV.